![]() In 2004, the NIH established its own NIH Chemical Genetics Center (NCGC), which became the National Center for Advancing Translational Sciences (NCATS) in 2008. In 2002, the National Cancer Institute established the Initiative for Chemical Genetics at the Broad Institute to support academic HTS with a particular focus on cancer therapies ( Tolliday et al., 2006). In addition, there was little extramural support for such work. Relatively few institutions had the wherewithal to create the infrastructure needed and to recruit the experienced staff to support academic research that utilized HTS as a method to identify compounds able to affect the activity of target proteins or pathways. High throughput screens (HTS) as part of drug development had long been the domain of large pharmaceutical companies, largely due to a lack of funding for such academic research, and only entered the academic sphere in the late 1990s. It is instead focused on two themes: 1) That there is a place for academic laboratories to make contributions to the discovery and development of PDE inhibitors using methods not traditionally employed by the pharmaceutical industry that has dominated this field, and 2) that the PDEs of parasitic organisms can serve as drug targets to treat infections that involve a host’s immune system and produce an inflammatory response (thus, an appropriate topic for this volume). This article is not intended to replace or repeat the many excellent reviews on these PDEs and their inhibitors. With regard to inflammation, therapeutic benefits have been demonstrated or proposed for inhibitors of PDE1, PDE2, PDE3, PDE4, PDE5, PDE7, PDE8, and PDE11 ( Bender and Beavo, 2006 Horvath et al., 2006 Vignozzi et al., 2013 Maurice et al., 2014 Pathak et al., 2017). Mammalian genomes possess 21 Class I PDE genes that are pharmacologically grouped into 11 families based on their specificity for cAMP and/or cGMP, structural features outside of the catalytic domains, and response to small molecules and other regulatory mechanisms. The signaling molecules 3’-5’ cyclic adenosine monophosphate (cAMP) and 3’-5’ cyclic guanosine monophosphate (cGMP) are produced by adenylyl and guanylyl cyclases, respectively, in response to external signals, and are hydrolyzed to 5’AMP and 5’GMP by cyclic nucleotide phosphodiesterases (PDEs). This allows for the discovery and profiling of PDE inhibitors to treat inflammation or of inhibitors of targets such as pathogen PDEs for which there may not be a sufficient financial motivation for pharmaceutical companies to identify selective PDE inhibitors using more traditional in vitro enzyme-based screening methods.Ĭyclic nucleotide signaling has been associated with a wide range of biological processes including oncogenesis, cognition, steroidogenesis, and inflammation, to name but a few ( Lerner and Epstein, 2006 Conti and Beavo, 2007). This screening method is readily accessible to academic laboratories as it does not require the purification of large quantities of a target protein. pombe also allows for molecular genetic screens to identify mutations in target PDE genes that confer some resistance to these inhibitors as a way of investigating the PDE-inhibitor interaction. Such compounds typically display the expected biological activity when tested in cell culture, including anti-inflammatory properties for PDE4 and PDE7 inhibitors. We have developed a platform for expressing cloned PDEs in the fission yeast Schizosaccharomyces pombe, allowing for inexpensive, but robust screening for small molecule inhibitors that are cell permeable. Mammalian genomes possess 21 genes whose products are pharmacologically grouped into 11 families however related genes from pathogenic organisms display sufficient divergence from the mammalian homologs such that PDE inhibitors to these enzymes could be used to treat parasitic infections without acting on the related human PDEs. Biology Department, Boston College, Chestnut Hill, MA, United StatesĬyclic nucleotide phosphodiesterases (PDEs) have been proven to be targets for which highly selective and potent drugs can be developed.
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